Neuroactive Kynurenines as Pharmacological Targets: New Experimental Tools and Exciting Therapeutic Opportunities.

Both preclinical and clinical studies implicate functional impairments of several neuroactive metabolites of the kynurenine pathway (KP), the major degradative cascade of the essential amino acid tryptophan in mammals, in the pathophysiology of neurologic and psychiatric diseases. A number of KP enzymes, such as tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenases (IDO1 and IDO2), kynurenine aminotransferases (KATs), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3-HAO), and quinolinic acid phosphoribosyltransferase (QPRT), control brain KP metabolism in health and disease and are therefore increasingly considered to be promising targets for the treatment of disorders of the nervous system. Understanding the distribution, cellular expression, and regulation of KP enzymes and KP metabolites in the brain is therefore critical for the conceptualization and implementation of successful therapeutic strategies.

Reducing brain kynurenic acid synthesis precludes kynurenine-induced sleep disturbances.

Patients with neurocognitive disorders often battle sleep disturbances. Kynurenic acid is a tryptophan metabolite of the kynurenine pathway implicated in the pathology of these illnesses. Modest increases in kynurenic acid, an antagonist at glutamatergic and cholinergic receptors, result in cognitive impairments and sleep dysfunction.

The stress of losing sleep: Sex-specific neurobiological outcomes.

Sleep is a vital and evolutionarily conserved process, critical to daily functioning and homeostatic balance. Losing sleep is inherently stressful and leads to numerous detrimental physiological outcomes. Despite sleep disturbances affecting everyone, women and female rodents are often excluded or underrepresented in clinical and pre-clinical studies.

Kynurenine aminotransferase II inhibition promotes sleep and rescues impairments induced by neurodevelopmental insult.

Dysregulated sleep is commonly reported in individuals with neuropsychiatric disorders, including schizophrenia (SCZ) and bipolar disorder (BPD). Physiology and pathogenesis of these disorders points to aberrant metabolism, during neurodevelopment and adulthood, of tryptophan via the kynurenine pathway (KP). Kynurenic acid (KYNA), a neuroactive KP metabolite derived from its precursor kynurenine by kynurenine aminotransferase II (KAT II), is increased in the brains of individuals with SCZ and BPD.

Application of Machine Learning to Sleep Stage Classification.

Sleep studies are imperative to recapitulate phenotypes associated with sleep loss and uncover mechanisms contributing to psychopathology. Most often, investigators manually classify the polysomnography into vigilance states, which is time-consuming, requires extensive training, and is prone to inter-scorer variability. While many works have successfully developed automated vigilance state classifiers based on multiple EEG channels, we aim to produce an automated and openaccess classifier that can reliably predict vigilance state based on a single cortical electroencephalogram (EEG) from rodents to minimize the disadvantages that accompany tethering small animals via wires to computer programs.

Time of Day-Dependent Alterations in Hippocampal Kynurenic Acid, Glutamate, and GABA in Adult Rats Exposed to Elevated Kynurenic Acid During Neurodevelopment.

Hypofunction of glutamatergic signaling is causally linked to neurodevelopmental disorders, including psychotic disorders like schizophrenia and bipolar disorder. Kynurenic acid (KYNA) has been found to be elevated in postmortem brain tissue and cerebrospinal fluid of patients with psychotic illnesses and may be involved in the hypoglutamatergia and cognitive dysfunction experienced by these patients. As insults during the prenatal period are hypothesized to be linked to the pathophysiology of psychotic disorders, we presently utilized the embryonic kynurenine (EKyn) paradigm to induce a prenatal hit.

Estradiol influences adenosinergic signaling and nonrapid eye movement sleep need in adult female rats.

Gonadal steroids and gender are risk factors for sleep disruptions and insomnia in women. However, the relationship between ovarian steroids and sleep is poorly understood. In rodent models, estradiol (E2) suppresses sleep in females suggesting that E2 may reduce homeostatic sleep need.

Prenatal Kynurenine Elevation Elicits Sex-Dependent Changes in Sleep and Arousal During Adulthood: Implications for Psychotic Disorders.

Dysregulation of the kynurenine pathway (KP) of tryptophan catabolism has been implicated in psychotic disorders, including schizophrenia and bipolar disorder. Kynurenic acid (KYNA) is a KP metabolite synthesized by kynurenine aminotransferases (KATs) from its biological precursor kynurenine and acts as an endogenous antagonist of N-methyl-D-aspartate and α7-nicotinic acetylcholine receptors. Elevated KYNA levels found in postmortem brain tissue and cerebrospinal fluid of patients are hypothesized to play a key role in the etiology of cognitive symptoms observed in psychotic disorders.

Exposure to elevated embryonic kynurenine in rats: Sex-dependent learning and memory impairments in adult offspring.

Distinct abnormalities in kynurenine pathway (KP) metabolism have been reported in various psychiatric disorders, including schizophrenia (SZ). Kynurenic acid (KYNA), a neuroactive metabolite of the KP, is elevated in individuals diagnosed with SZ and has been linked to cognitive impairments seen in the disorder. To further understand the role of KYNA in SZ etiology, we developed a prenatal insult model where kynurenine (100 mg/day) is fed to pregnant Wistar rats from embryonic day (ED) 15 to ED 22.

Acute sleep deprivation during pregnancy in rats: Rapid elevation of placental and fetal inflammation and kynurenic acid.

The kynurenine pathway (KP) is the dominant pathway for tryptophan degradation in the mammalian body and emerging evidence suggests that acute episodes of sleep deprivation (SD) disrupt tryptophan metabolism via the KP. Increases in the neuroactive KP metabolite kynurenic acid (KYNA) during pregnancy may lead to a higher risk for disrupted neurodevelopment in the offspring. As pregnancy is a critical period during which several factors, including sleep disruptions, could disrupt the fetal environment, we presently explored the relationship between maternal SD and KP metabolism and immune pathways in maternal, placenta, and fetal tissues.

Peripheral Cortisol and Inflammatory Response to a Psychosocial Stressor in People with Schizophrenia.

Objectives: There is growing evidence of both hypothalamic-pituitary-adrenal (HPA) axis and immune system dysfunction in schizophrenia. Additionally, accumulating evidence has linked dysfunction in the kynurenine pathway to schizophrenia as well as to stress and inflammation. The current pilot tested changes in immune, cortisol and kynurenine and kynurenic acid responses to a psychosocial stressor in people with schizophrenia and healthy controls.

Inhibition of kynurenine aminotransferase II attenuates hippocampus-dependent memory deficit in adult rats treated prenatally with kynurenine.

A combination of genetic and environmental factors contributes to schizophrenia (SZ), a catastrophic psychiatric disorder with a hypothesized neurodevelopmental origin. Increases in the brain levels of the tryptophan metabolite kynurenic acid (KYNA), an endogenous antagonist of α7 nicotinic acetylcholine and NMDA receptors, have been implicated specifically in the cognitive deficits seen in persons with SZ. Here we evaluated this role of KYNA by adding the KYNA precursor kynurenine (100 mg/day) to chow fed to pregnant rat dams from embryonic day (ED) 15 to ED 22 (control: ECon; kynurenine treated: EKyn).

A High-performance Liquid Chromatography Measurement of Kynurenine and Kynurenic Acid: Relating Biochemistry to Cognition and Sleep in Rats.

The kynurenine pathway (KP) of tryptophan degradation has been implicated in psychiatric disorders. Specifically, the astrocyte-derived metabolite kynurenic acid (KYNA), an antagonist at both N-methyl-d-aspartate (NMDA) and α7 nicotinic acetylcholine (α7nACh) receptors, has been implicated in cognitive processes in health and disease. As KYNA levels are elevated in the brains of patients with schizophrenia, a malfunction at the glutamatergic and cholinergic receptors is believed to be causally related to cognitive dysfunction, a core domain of the psychopathology of the illness.

Exercise Your Kynurenines to Fight Depression.

Kynurenines, the major degradative products of the essential amino acid tryptophan, may play critical roles in the pathophysiology of depressive disorders. In 2014, Agudelo and colleagues reported that exercise indirectly modulates the metabolism of kynurenines in skeletal muscle, which in turn influences the brain and enhances resilience to depression.

Salivary kynurenic acid response to psychological stress: inverse relationship to cortical glutamate in schizophrenia.

Frontal glutamatergic synapses are thought to be critical for adaptive, long-term stress responses. Prefrontal cortices, including the anterior cingulate cortex (ACC) contribute to stress perception and regulation, and are involved in top-down regulation of peripheral glucocorticoid and inflammatory responses to stress. Levels of kynurenic acid (KYNA) in saliva increase in response to psychological stress, and this stress-induced effect may be abnormal in people with schizophrenia.

Sex Differences in Hippocampal Memory and Kynurenic Acid Formation Following Acute Sleep Deprivation in Rats.

Inadequate sleep is a prevalent problem within our society that can result in cognitive dysfunction. Elevations in kynurenic acid (KYNA), a metabolite of the kynurenine pathway (KP) of tryptophan degradation known to impact cognition, in the brain may constitute a molecular link between sleep loss and cognitive impairment. To test this hypothesis, we investigated the impact of 6 hours of sleep deprivation on memory and KP metabolism (brain and plasma) in male and female rats.

Influence of plasma cytokines on kynurenine and kynurenic acid in schizophrenia.

Abnormalities in the kynurenine pathway (KP) of tryptophan degradation, leading to the dysfunction of neuroactive KP metabolites in the brain, have been implicated in the pathophysiology of schizophrenia (SZ). One plausible mechanism involves dysregulation of various pro-inflammatory cytokines associated with the disease, which affect indoleamine-2,3-dioxygenase (IDO), a key enzyme for tryptophan to kynurenine conversion. In order to test this hypothesis directly, we measured plasma levels of the major KP metabolites kynurenine and kynurenic acid (KYNA), as well as four major cytokines, in a sample of 106 SZ patients and 104 control participants.

Basic Neuroscience Illuminates Causal Relationship Between Sleep and Memory: Translating to Schizophrenia.

Patients with schizophrenia are often plagued by sleep disturbances that can exacerbate the illness, including potentiating psychosis and cognitive impairments. Cognitive dysfunction is a core feature of schizophrenia with learning and memory being particularly impaired. Sleep disruptions often accompanying the illness and may be key mechanism that contribute to these core dysfunctions.

Prenatal kynurenine treatment in rats causes schizophrenia-like broad monitoring deficits in adulthood.

Rationale: Elevated brain kynurenic acid (KYNA) levels are implicated in the pathology and neurodevelopmental pathogenesis of schizophrenia. In rats, embryonic treatment with kynurenine (EKyn) causes elevated brain KYNA levels in adulthood and cognitive deficits reminiscent of schizophrenia.

Objectives: Growing evidence suggests that people with schizophrenia have a narrowed attentional focus, and we aimed at establishing whether these abnormalities may be related to KYNA dysregulation.

Prenatal Dynamics of Kynurenine Pathway Metabolism in Mice: Focus on Kynurenic Acid.

The kynurenine pathway (KP), the major catabolic route of tryptophan in mammals, contains several neuroactive metabolites, including kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK). KP metabolism, and especially the fate of KYNA, during pregnancy is poorly understood, yet it may play a significant role in the development of psychiatric disorders later in life. The present study was designed to investigate the prenatal features of KP metabolism in vivo, with special focus on KYNA.

Acute Kynurenine Challenge Disrupts Sleep-Wake Architecture and Impairs Contextual Memory in Adult Rats.

Study Objectives: Tryptophan metabolism via the kynurenine pathway may represent a key molecular link between sleep loss and cognitive dysfunction. Modest increases in the kynurenine pathway metabolite kynurenic acid (KYNA), which acts as an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors in the brain, result in cognitive impairments. As glutamatergic and cholinergic neurotransmissions are critically involved in modulation of sleep, our current experiments tested the hypothesis that elevated KYNA adversely impacts sleep quality.